Co-crystals are solid-state, crystalline materials that are composed of two or more molecules in the same crystal lattice. Co-crystals are distinguishable from other pharmaceutical solid-state forms, such as polymorphs or salts, as these other solid-state forms only contain the active pharmaceutical ingredient (“API”) within the crystal lattice, whereas co-crystals are composed of an API with a guest compound in the crystal lattice. Two or more of the molecules in a co-crystal are, neutral, interact via nonionic interactions, and are solids at room temperature when isolated as individual components
Typically, co-crystals are prepared by crystallizing an API with a guest compound. Guest compounds are compounds that possess the ability to form complementary non-covalent interactions with the API. General classes of guest compounds include compounds having alcohol, ketone, ester and/or carboxylic acid functionalities. Co-crystals of different APIs are known in the art. See, e.g., U.S. Pat. No. 8,163,790 B2; U.S. Pat. No. 8,097,593; U.S. Pat. Nos. 8,003,700 and 8,039,475, Co-crystals form in situations where favorable interactions between the individual components exist and one might expect to see improved physical properties, such as solubility, hygroscopicity and compaction behavior. Sekhon, ARS Pharm., 50(3), pp 99-117 (2009).
Thrombin is known to have a variety of activities in different cell types. PAR-1 receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is expected that PAR-1 receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Substituted bi- and tricyclic thrombin receptors antagonists are known in the art and the art suggests that these receptor antagonists will treat thrombin receptor mediated disorders such as thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, angiogenesis related disorders, arrhythmia, a cardiovascular or circulatory disease or condition, heart failure, ACS, MI, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, PAL), deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome and cerebral infarction, as well as CB2 receptor mediated disorders. See, e.g., U.S. Pat. No. 7,304,048 or U.S. Pat. No. 6,645,987, U.S. Pat. No. 6,645,987 and U.S. Pat. No. 6,894,065 disclose PAR-1 receptor antagonists of the structure:
where R10 may be groups such as H, alkyl, haloalkyl, hydroxyl, etc, and R22 may be groups such as H, optionally substituted alkyl, hydroxyl, etc. Other known substituted thrombin receptor antagonists are disclosed in U.S. Pat. No. 6,063,847, U.S. Pat. No. 6,326,380, U.S. Pat. No. 7,037,920, U.S. Pat. No. 7,488,742, U.S. Pat. No. 7,713,999, U.S. Pat. No. 7,442,712, U.S. Pat. No. 7,488,752, U.S. Pat. Nos. 7,776,889, 7,888,369, U.S. Pat. No. 8,003,803, U.S. Pat. No. 8,022,088, US 2008/0090830, and Chackalamannil et al., J. Med. Chem., 49, p. 5389 (2006).
A PAR-1 receptor antagonist that exhibits good thrombin receptor antagonist activity (potency) and selectivity is vorapaxar (Merck & Co., Inc.), which has the following structure:
This compound has undergone clinical trials (TRA-CER and TRA 2°P) and is disclosed in U.S. Pat. No. 7,304,048. U.S. Pat. No. 7,235,567 discloses the bisulfate salt of vorapaxar and indicates that this salt has at least two crystalline polymorphic forms; viz., Form 1 and Form 2. FIG. 1 is a powder x-ray diffraction (PXRD) pattern of Form 1 of the bisulfate salt of vorapaxar and FIG. 2 is a PXRD of Form 2. U.S. Pat. No. 7,235,567 indicates that Form 2 was found to be unstable and reverted over time to the crystalline structure of Form 1. An advantage of the inventive co-crystal is that they do not exist in other polymorphic forms or form solvates.
U.S. Patent Applications US 2008/0026050 A1; US 2008/0031943 A1; and US 2008/0152712 A1 disclose capsule formulations, tablet formulations and lyophilized formulations (respectively) of vorapaxar or a pharmaceutically acceptable salt thereof as well methods of treating various conditions affected by antagonizing the PAR-1 receptor by administering same to a patient. U.S. Pat. No. 7,304,048 and U.S. Pat. No. 7,235,567 describe inter alia pharmaceutical combinations of vorapaxar and aspirin. Other pharmaceutical combinations of vorapaxar and other cardiovascular agents are described in US 2007/023874 A1.
There is a need to develop pharmaceutical formulations comprising vorapaxar as an active agent wherein vorapaxar exhibits polymorphic simplicity (i.e., does not form other polymorphic forms or solvates). This and other objectives will become evident from the following description.